Objective: To investigate whether curcumin alleviates septic lung injury by inhibiting ferroptosis through modulating the TXNIP/TRX-1/GPX4 pathway.
Methods: Male C57BL/6 mice were randomly divided into Sham group, cecal ligation puncture (CLP)-induced sepsis group, CLP with curcumin treatment (50, 100, and 200 mg/kg) groups, and CLP with both curcumin (200 mg/kg) and TRX-1 inhibitor PX-12 (25 mg/kg) treatment group. Inflammatory factors, MDA, MPO, and GSH levels in the lung tissue of the mice were detected. Beas-2B cells stimulated with lipopolysaccharide (LPS; 1 μg/mL) were treated with 2.5, 5, or 10 μmol/L curcumin or with 10 μmol/L curcumin combined with 5 μmol/L PX-12, and the changes in MDA, Fe2+ and ROS levels were assessed. Western blotting was performed to detect the protein expressions of TXNIP, TRX-1, GPX4 and X-CT in both the mouse lung tissues and Beas-2B cells.
Results: The mice with CLP-induced sepsis showed severe lung injury with elevated expressions of IL-6, IL-1β, TNF-α, MDA and MPO and decreased GSH expression. In Beas-2B cells, LPS stimulation significantly increased MDA and Fe2+ levels and ROS release, increased TXNIP protein expression, and lowered the protein expression levels of TRX-1, GPX4 and X-CT, and these changes were also observed in the septic mice. Curcumin treatments at different concentrations obviously alleviated lung injury in the septic mice and reduced LPS-induced injury in Beas-2B cells. Curcumin significantly decreased the release of inflammatory factors, MDA and MPO, increased GSH level, lowered Fe2+, MDA and ROS levels, increased TXNIP protein expression, and lowered the protein expressions of TRX-1, GPX4 and X-CT in both septic mouse lung tissues and LPS-stimulated Beas-2B cells. The protective effect of curcumin was effectively blocked by PX-12 treatment.
Conclusion: Curcumin inhibits ferroptosis and alleviates septic lung injury in mice by elevating TRX-1 and GPX4 and decreasing TXNIP in the lung tissue.
Keywords: TXNIP/TRX-1/GPX4 pathway; curcumin; ferroptosis; sepsis lung injury.